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Ischaemic heart disease (IHD) is normally the result of atherosclerosis in the coronary arteries. Atherosclerosis is a disease of the arterial intima, and starts as focal deposition of lipid material and inflammatory cells. When these lipid laden lesions become advanced, they may become stenosing (i.e. cause narrowing of the blood vessel) and can thus limit blood flow to parts of the myocardium. Atherosclerosis occurs also in other arteries and can lead to stenosis in the vessels to especially the legs, brain and kidneys. This blood flow limitation can cause ischaemic pain, such as angina pectoris and intermittent claudication.
Another consequence of atherosclerosis is that the lesions can become unstable and rupture, leading to the formation of an arterial thrombus at the site of rupture. This thrombus severely compromises oxygen supply to the downstream tissue and will, unless the thrombus is resolved, lead to infarction of the ischaemic tissue (myocardial infarction, stroke, etc.). Myocardial infarction and stroke are the two most common causes of death worldwide.
Restoring normal blood supply to ischaemic tissue is the most important acute goal for the treatment of ischaemic disorders, this can be achieved by medication or by intervention. In patients with acute arterial thrombotic events such as acute myocardial infarction, it is important to restore blood flow to the ischaemic tissue as quickly as possible, in order to reduce the consequences of the thrombotic event, and surgical intervention is common in this situation. Patients with stable angina pectoris or other ischaemic disorders that cannot be adequately controlled with drugs can also be treated surgically.
Surgical interventions, such as for coronary revascularisation, are performed by either bypass grafting (such as coronary artery bypass grafting, CABG) or by catheter based interventions. In the case of bypass surgery such as CABG, a mammary artery is exposed, its distal end removed from the breast and sutured into a position distal to the stenosed segment of the coronary artery, thus allowing perfusion of the ischaemic tissue. If the mammary artery cannot be used, or if multiple bypasses are required, the surgeon will use veins from the legs (vein grafts). In this case, a vein segment is removed and placed from the aorta to a position distal to the stenosis.
During catheter based interventions, such as PCI (percutaneous coronary intervention), a balloon catheter is typically inserted through a femoral artery and guided into the stenotic segment, where the balloon is inflated and the stenotic segment thus dilated. This is also known as balloon angioplasty. Other procedures that are done during PCI may include implantation of a stent, or atherectomy, such as rotational or laser atherectomy (removal of atheromatous plaque material). To improve efficacy of the intervention, a stent catheter can be used to implant a stent. In this case, the catheter will also place a metal stent to support the artery wall to maintain lumen calibres.
Interventions intended to restore normal blood flow to ischemic tissue can result in restenosis, caused by the formation of a neointima or neointimal thickening. The underlying cause is vascular smooth muscle injury and disruption of the integrity of the endothelial lining. The process is also characterised by the presence and activity of inflammatory cells and eventual co-morbidities the patient suffers. The underlying molecular mechanisms of the processes of development of the primary stenosis and the secondary restenosis are different, but there is considerable overlap between the two.
Bypass grafting is an effective intervention, but a common complication is the so called restenosis, the rapid development of a neointima that will lead to the formation of a new stenosis in the graft vessel, often resulting in the need to perform a repeat revascularisation procedure. This is especially common in vein grafts, where approximately 15% of grafts occlude during the first year, and by 10 years 50% of the graft vessels are stenotic (Motwani and Topol, 1998). Vein graft failure can be considered as an injury-induced inflammatory disease, including macrophage infiltration and activation and medial smooth muscle cell activation (Zhang et al., 2004).
Also after PCI is restenosis a common complication. It is more common to perform a repeat revascularisation procedure after PCI than after CABG; the absolute rates at 5 years were 46.1% after balloon angioplasty, 40.1% after PCI with stents, and 9.8% after CABG (Bravata et al., 2007).
Proliferation of smooth muscle cells of a matrix synthesising phenotype is an important factor in the process leading to neointima formation. A recent development that effectively reduces restenosis is the so called drug eluting stents (DES). These stents are coated with polymers that contain cytostatic agents (e.g., rapamycin), that effectively inhibits the proliferative response to the surgical intervention. In patients receiving DES, restenosis occurs typically with an incidence below 4%. However, the DES stents do not become fully integrated into the vessel wall, and they are associated with an increased risk for thrombus formation, that cannot be effectively controlled with drugs. In fact, the advantage of DES as concerns restenosis do not lead to a significant improvement in prognosis for the patient, as increased risk for thrombosis offsets this effect. In fact, there are now recommendations to use DES with caution, and recommendations to increase anti-thrombotic therapy has also been issued (Smith et al., 2006).
The restenotic lesions are inflammatory lesions that at least superficially have similarities to the primary atherosclerotic lesions. The dominating cells are smooth muscle cells, but also macrophages/foam cells and T-lymphocytes are present in restenosis lesions. CABG and PCI are effective treatments for stenosis, and there has been some advantage in medical approaches to limit intervention associated complications, but effective treatments that prevent restenosis effectively would further improve the treatment. Even in the case of DES, it would be an advantage if the stents could be coated with an effective anti-restenotic agent that does not lead to an increased risk for the formation of arterial thrombi.
From the above summary, it becomes evident that an effective treatment that reduces the formation of restenosis is a therapeutic opportunity for disease conditions where revascularisation procedures are performed, independent of whether the technique used to obtain revascularisation is bypass grafting or by balloon dilatation of the stenosed vessel segment, with or without stent placement.
Annexin A5 is an endogenous protein that binds to charged phospholipids such as phosphatidylserine (PS) (Cederholm and Frostegard, 2007). Annexin A5 is a potent anti-thrombotic agent (Thiagarajan and Benedict, 1997), and it is proposed that Annexin A5 by binding to exposed PS can form a ‘protective shield’ that can inhibit the effects of PS on thrombosis formation (Rand, 2000).
It has been shown that in addition to anti-platelet and anti-coagulant effects of Annexin A5, this protein and an analogue thereof, the Annexin A5 dimer diannexin, is effective in preventing reperfusion injury in the liver (Teoh et al., 2007), and it improved the outcome of rat liver transplants (Shen et al., 2007). Interestingly, in both these studies the treatments were associated with a reduced inflammatory activity in the hepatic endothelium, measured as reduced expression of adhesion molecules, that is Annexin A5 has anti-inflammatory effects. It was suggested that diannexin improved the survival of the liver transplants by an anti-thrombotic effect leading to maintained blood supply to the liver (Shen et al., 2007). It has earlier been suggested that Annexin A5 can be used to stabilise atherosclerotic lesions in coronary arteries in patients, which should reduce the risk for myocardial infarction in these patients (Cederholm et al., 2005; WO 2005/099744).